The growth and invasiveness of solid tumors is highly dependent on angiogenesis or the processes forming new tumor blood vessels. Accordingly the development of antiangiogenic drugs is of considerable importance, yet recent clinical trials have demonstrated that early favorable patient responses are not durable, which has been attributed to drug resistance. The complex and diverse nature of the drug resistance mechanisms calls for a systematic approach to define new treatment paradigms to alleviate resistance to angiogenesis inhibitors. The overall objective of the project is to provide a preclinical foundation to design multidrug combination regimens that will overcome resistance to angiogenesis inhibitors and further ensure that coadministered cytotoxic drugs will reach tumors in sufficient amounts. To accomplish this objective, three Aims are proposed that describe a series of pharmacokinetic (PK) and pharmacodynamic (PD) investigations based on the properties of the drugs in tumors. Aim 1 studies will derive antiangiogenic drug resistant brain tumors in vivo and compare the tumor accumulation of the cytotoxic drug, temozolomide (TMZ) in sensitive and resistant tumors. The expression of genes and proteins relevant to angiogenesis will be monitored to create a resistance profile. Initial Aim 2 studies, again utilizing drug resistant tumors, will evaluate multitargeted drug combinations that interfere with angiogenesis by inhibiting targets on the cell surface and intracellularly. The drug combinations selected will be, in part, based on the resistance profiles determined in Aim 1. Upon identifying multitargeted drug combinations that suppress resistance, a final set of studies will be undertaken to analyze TMZ tumoral delivery and the process referred to as vascular normalization, a hallmark of effective drug delivery. As in Aim 1, PK (i.e. drug concentrations) and PD (gene and protein expression) measurements will be obtained in Aim 2 to provide a robust database to formulate PK/PD models for the effective combinations, which is the goal of Aim 3. Specifically, we will build physiologically-based PK/PD models that offer a means to be extrapolated to patients so that PK and PD endpoints can be predicted in brain tumors. The quantitative pharmacological approach underlying the project enables a more seamless pipeline of information to flow into the clinic that hopefully will provide a rational paradigm to design complex multidrug regimens.